With the changes into European and American life styles and the increase in aged population in recent years, the number of patients with thromboembolic diseases including myocardial infarction, cerebral thrombosis and peripheral arterial thrombosis have been increasing year by year and social importance of their treatment has been increasing more and more. As well as the fibrinolysis therapy and antiplatelet therapy, the anticoagulation therapy takes a part of the medical therapy in treating and preventing thrombosis (Sogo Rinsho, 41: 2141-2145, 1989). In particular, the safety which withstands long-term administration and accurate and proper expression of the anticoagulation activity are essential in the prevention of thrombosis. Warfarin potassium is frequently used in the world as the sole oral anticoagulant but this drug is extremely difficult to use clinically because it is difficult to control the anticoagulation capacity due to the characteristics based on its action mechanism (J. Clinical Pharmacology, 32, 196-209, 1992 and N. Eng. J. Med., 324(26), 1865-1875, 1991) whereby a great concern has been directed toward the development of more useful and easily usable anticoagulants.
Thrombin controls conversion of fibrinogen into fibrin which is the final step of coagulation and is also concerned deeply in the activation and aggregation of platelets (“T-PA and Pro-UK” edited by S. Matsuo, published by Gakusai Kikaku, pp. 5-40 “Blood Coagulation”, 1986) and its inhibitor has been the center of anticoagulant studies as a target of development of pharmaceuticals. However, thrombin inhibitors which can be administered orally have not been put into the market until now because of their low bioavailability by oral administration and problems from the viewpoint of safety (Biomed. Biochim. Acta, 44, 1201-1210, 1985).
Activated blood coagulation factor X is a key enzyme which is located at the joining point of the extrinsic and intrinsic coagulation cascade reactions and located upstream to thrombin whereby there is a possibility that inhibition of this factor is more efficient than the thrombin inhibition and such an inhibitor can inhibit this coagulation system in a specific manner (THROMBOSIS RESEARCH (19), 339-349, 1980).
As the compounds having an activated blood coagulation factor X inhibiting action, amidinonaphthyl alkylbenzene derivatives or salts thereof have been known (Japanese Patent Laid-Open No. 208946/1993; Thrombosis Haemostasis, 71(3), 314-319, 1994; and Thrombosis Haemostasis, 72(3), 393-396, 1994).
In WO 96/16940, it is mentioned that an amidinonaphthyl derivative or a salt thereof represented by the following formula is the compound having an activated blood coagulation factor X inhibiting action.
(for the symbols in the formula, refer to the gazette)
In WO 99/00121, WO 99/00126, WO 99/00127, WO 99/00128, WO 00/39111, WO 00/39117 and WO 00/39118, phenylenediamide compounds represented by the following formula, etc. are mentioned as an Xa factor inhibitor.
(for the symbols in the formula, refer to each of the gazettes)
Further, in WO 99/32477, a broad range of compounds represented by the following formula is mentioned as an anticoagulant.
(for the symbols in the formula, refer to the gazette)
In an anticoagulation therapy, activated blood coagulation factor X inhibitor is expected to inhibit coagulation system effectively and specifically as compared with a thrombin inhibitor. Accordingly, there has been a brisk demand for creating a selective activated blood coagulation factor X inhibitor which has different chemical structure from the above-mentioned known compounds, is able to be administered per os and has further excellent effect.